Network targeting combination therapy of synthetic lethal vulnerabilities in 9p21-deficient glioblastoma: A case report.

Background: Patients with relapsed or progressive glioblastoma only rarely respond to salvage therapies. Nevertheless, comprehensive genomic profiling can provide insight that can identify promising approaches. Signaling pathway analyses have revealed synthetic lethal partnerships, which create the possibility of targeting vulnerabilities arising from the loss of tumor suppressor genes. For synthetic lethal vulnerabilities that are not present in normal tissues, lethal cytotoxicity against cancer cells can be achieved without the necessity of causing normal tissue toxicity. This case report describes a patient with progressive glioblastoma with homozygous deletion of chromosome 9p21. Methods and Results: Vulnerabilities created by CDKN2A and MTAP loss were exploited with pemetrexed, bevacizumab, and candesartan to achieve a clinically meaningful remission by targeting multiple synthetic lethal nodes. Conclusion: Synthetic lethality can reveal the basis for exceptional responsiveness, thus extending the utility of molecular profiling and fulfilling the promise of precision medicine.

Network-targeting combination therapy of leptomeningeal glioblastoma using multiple synthetic lethal strategies: a case report.

Network targeting of disease-specific nodes represents a useful principle for designing combination cancer therapy. In this case of a patient with relapsed leptomeningeal glioblastoma, comprehensive molecular diagnosis led to the identification of a disease network characterized by multiple disease-specific synthetic lethal vulnerabilities involving DNA repair, REDOX homeostasis, and impaired autophagy which suggested a novel network-targeting combination therapy (NTCT). A treatment regimen consisting of lomustine, olaparib, digoxin, metformin, and high dose intravenous ascorbate was employed using the principle of intra-patient dose escalation to deliver the treatment with adequate safety measures to achieve a definitive clinical result.

Targeting chromosome 12q amplification in relapsed glioblastoma: the use of computational biological modeling to identify effective therapy-a case report.

Background: Relapsed glioblastoma (GBM) is often an imminently fatal condition with limited therapeutic options. Computation biological modeling, i.e., biosimulation, of comprehensive genomic information affords the opportunity to create a disease avatar that can be interrogated in silico with various drug combinations to identify the most effective therapies. Case Description: We report the outcome of a GBM patient with chromosome 12q amplification who achieved substantial disease remission from a novel therapy using this approach. Following next generation sequencing (NGS) was performed on the tumor specimen. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotype. In silico responses to various drug combinations were biosimulated in the disease network. Efficacy scores representing the computational effect of treatment for each strategy were generated and compared to each other to ascertain the differential benefit in drug response from various regimens. Biosimulation identified CDK4/6 inhibitors, nelfinavir and leflunomide to be effective agents singly and in combination. Upon receiving this treatment, the patient achieved a prompt and clinically meaningful remission lasting 6 months. Conclusions: Biosimulation has utility to identify active treatment combinations, stratify treatment options and identify investigational agents relevant to patients' comprehensive genomic abnormalities. Additionally, the combination of abemaciclib and nelfinavir appear promising for GBM and potentially other cancers harboring chromosome 12q amplification.

Mismatch repair deficiency associated with complete remission to combination programmed cell death ligand immune therapy in a patient with sporadic urothelial carcinoma: immunotheranostic considerations.

BACKGROUND: Mismatch repair deficiency (MMRD) is a common pathway of malignant transformation accounting for approximately 15-20 % of human carcinogensis. It has been postulated that MMRD increases tumor antigenicity and highlights a role for immunotherapeutic approach MMR-deficient cancers. This strategy was pursued in a patient with upper tract urothelial carcinoma, and the results are reported here. CASE PRESENTATION: Molecular profiling was performed using next generation DNA sequencing and (IHC) testing for MMR and PD-L1. A patient with sporadic, high grade urothelial carcinoma of the renal pelvis was found to have a hypermutator genotype with 73 mutations occurring amidst 62 known drivers of malignancy, and 340 VUS alterations. MMR deficiency phenotype was confirmed by the absence of MSH2 and MSH6 as well as deleterious mutations in these genes. IHC staining for programmed cell death ligand-1 [PD-L1] revealed 2+ staining in 80 % of cells. The patient gained access to combination immunotherapy trial utilizing MEDI4736 and MEDI0680 through a clinical trial. The patient achieved a prolonged, complete remission within two months and had no severe ill effects from the treatment. CONCLUSION: Given their ability to generate neo-antigens, MMR-deficient cancers may be uniquely susceptible to immune checkpoint inhibitor strategies, including urothelial tract cancers. Screening for MMR deficient cancers has the potential to become a routine strategy for evaluating the role of PD-L1 inhibitors for patient with advanced disease. ( TRIAL REGISTRATION: Clinicaltrials.gov NCT00938834. Registered 13 July 2009).

Successful use of next generation genomic sequencing (NGS)-directed therapy of clear cell carcinoma of the ovary (CCCO) with trametinib and metformin in a patient with chemotherapy-refractory disease.

PURPOSE: Compared to other subtypes of epithelial ovarian cancer, clear cell carcinoma of the ovary bears an ominous reputation for chemotherapy resistance, increased relapse rate, and diminished survival. Among patients with distinct histopathologic subtypes, molecular analyses have identified a variety of known drivers of the malignant behavior, and depict a striking heterogeneity. METHODS: A patient with rapidly metastatic CCCO that was refractory to taxane, platinum, pemetrexed, and bevacizumab-based strategies underwent molecular profiling which disclosed dual MAPK and PI3K/AKT/mTOR pathway mutations. RESULTS: Combined targeted therapy with trametinib and metformin resulted in a dramatic disease regression without toxicity. CONCLUSION: The case highlights the utility of precision medicine combining individual molecular diagnosis with rational therapeutic intervention with targeted agents.